The primary goal of the studies proposed is a better understanding of the role of the immune system in the regulation of both normal and pathological bone resorption. Recent studies have demonstrated that immune cells and the cytokines they produce can function in the regulation of bone resorption. This hypothesis will be assessed by investigating the relationship(s) between an immune defect in natural killer (NK) cell activity and a bone resorption defect in osteoclastic activity in the ia osteopetrotic rat. The skeletal disease, osteopetrosis, in the ia rat is characterized by a generalized excess accumulation of bone due to reduced bone resorption by defective osteoclasts. Although the osteoclasts in this mutant are functionally inactive, they are found in increased numbers - possibly as a compensatory response to their reduced function. A similar finding has been recently reported for NK cells in the ia mutant; NK cells were found in significantly greater numbers in ia mutants than normal control rats, but NK activity was only 50-70% of normal. The proposed studies will: 1) evaluate the functional capabilities of ia and normal NK cells in NK assays; 2) quantitate and morphologically analyze isolated NK cells by light and electron microscopy and enzyme histochemistry; 3) determine the mechanism of the defect, by evaluating ia NK cells in a single cell assay; 4) attempt to correct the NK defect by the transplantation of various bone marrow stem cells; and 5) attempt to correct the defect with the in vitro and in vivo administration of various cytokines. The research described will define the NK defect, compare it to the osteoclastic defects, and relate these two cells via a possible common lineage, a common mechanism of action, and/or a synergistic relationship. These studies should aid in the understanding of the mechanism of action of both normal and defective NK cells. The findings will also be of direct clinical relevance for the treatment of some forms of neonatal osteopetrosis. Recently an osteopetrotic child was described with reduced NK function, which was responsive to lymphokines. This information suggests that there is a defect in lymphokine production which may associated with the decreased osteoclastic function. These studies should clarify this concept and provide rationale for the clinical management of such children. The proposed studies should also provide the framework for future investigations of the role of the immune system in bone resorption.